Until recently, management of metabolic-associated steatohepatitis (MASH) relied on weight loss and increased exercise. Given the strong association between obesity and MASH, sustained weight loss remains a cornerstone of treatment. Studies show that a weight reduction of just 3% to 5% can reduce liver fat, while a 10% or more decrease resolves MASH in 90% of patients, with 45% seeing regression in fibrosis.[1]
Another aspect of diet may also reduce the risk of MASH and development of fibrosis – coffee. A meta-analysis revealed that drinking two or more cups of caffeinated coffee per day reduced the relative risk of liver fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), the precursor to MASH, by 32%.[2]
First FDA-approved pharmacotherapy
In March 2024, the U.S. FDA approved resmetirom, the first pharmacotherapy for patients with MASH and stage 2 or 3 fibrosis, the patients at most risk of cirrhosis, hepatocellular carcinoma and liver-related mortality.
“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of [resmetirom] will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”[3] MASH was previously known as non-alcoholic steatohepatitis (NASH).
Resmetirom acts as a partial activator of a thyroid hormone receptor beta agonist that regulates lipid metabolism in the liver. By activating this thyroid hormone receptor, resmitirom reduces liver fat.[4] In the pivotal trial, up to 29.9% of participants treated with resmitirom achieved NASH resolution and no increase in liver scarring, and up to 28% experienced a reduction in liver fibrosis with no worsening of MASH.[5]
Emerging and repurposed therapies for MASH
Several medications for diabetes also improve MASH, but fewer appear to reduce fibrosis. These include pioglitazone, a thiazolidinedione, and glucagon-like peptide 1 (GLP-1) receptor agonists.
In a three-year study, 58% of trial participants who took 45 mg of pioglitazone per day in combination with a 500 kcal per day deficit diet achieved a two-point drop in their MASLD activity score in two categories and 51% resolved MASH entirely compared to 19% of those randomized to diet only. Pioglitazone reduced mean fibrosis scores, but not statistically significantly, and reduced fibrosis progression compared to placebo, 12% vs. 28%, respectively, (p=0.039).[6] Pioglitazone can cause or worsen heart failure, lead to weight gain, accelerate loss of bone density, damage the liver and increase the risk of bladder cancer.[7]
Semaglutide, a GLP-1 agonist, did not demonstrate improvement in fibrosis in patients with MASH in a 48-week phase 2 trial.[8]
Two other GLP-1 receptor agonists—tirzepatide and retatrutide—showed positive results, however. A phase 2 trial of tirzepatide with 190 participants who had biopsy-confirmed MASH and stage 2 or 3 fibrosis found that 44% to 62% of those receiving tirzepatide achieved resolution of MASH without worsening of fibrosis compared to 10% of those receiving placebo at 52 weeks. In addition, between 51% and 55% of those in the tirzepatide group saw a one stage or better improvement in fibrosis without worsening of MASH compared to 30% in the placebo group.[9]
Retatrutide, a novel triple agonist of GLP-1, glucagon receptors and glucose-depended insulinotropic polypeptide, recently demonstrated outstanding results in resolving MASLD, with 86% of participants achieving less than 5% liver fat in just 24 weeks. Studies evaluating retatrutide’s ability to reduce fibrosis are underway.[10]
Pegozafermin, a long-acting glycopegylated fibroblast growth factor analogue, has also shown some promise in MASH with stage 2 or 3 fibrosis. In a phase 2b trial, fibrosis improved by one stage or more in 22% to 27% of participants who received pegozafermin over 24 weeks compared to 7% in the placebo group. MASH resolved in 23% to 37% of the pegozafermin group and 2% of the placebo group.[11]
With the approval of resmetirom and the development of additional promising therapies, treatment options for MASH are rapidly expanding, offering new hope to patients with advanced liver disease.
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